title: Tanshinone IIA induces autophagic cell death via activation of AMPK and ERK and inhibition of mTOR and p70 S6K in KBM-5 leukemia cells.
abstract: Although tanshinone IIA (Tan IIA) from Salviae miltiorrhizae was known to induce apoptosis in various cancers, its underlying mechanism of autophagic cell death was not reported yet. Thus, in the present study, the molecular mechanism of autophagic cell death by Tan IIA was investigated in KBM-5 leukemia cells. Tan IIA significantly increased the expression of microtubule-associated protein light chain 3 (LC3) II as a hallmark of autophagy in western blotting and immunofluorescence staining. Tan IIA augmented the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and attenuated the phosphorylation of mammalian target of rapamycin (mTOR) and p70 S6K in a dose-dependent manner. Conversely, autophagy inhibitor 3-methyladenine partly reversed the cytotoxicity and the phosphorylation of AMPK, mTOR and p70 S6K induced by Tan IIA in KBM-5 leukemia cells. In addition, Tan IIA dramatically activated the extracellular signal regulated kinase (ERK) signaling pathway including Raf, ERK and p90 RSK in a dose-dependent and time-dependent manner. Consistently, ERK inhibitor PD184352 suppressed LC3-II activation induced by Tan IIA, whereas PD184352 and PD98059 did not affect poly (ADP-ribose) polymerase cleavage and sub-G1 accumulation induced by Tan IIA in KBM-5 leukemia cells. Furthermore, Tan IIA could induce autophagy via LC3-II activation in various cancer cells such as prostate (PC-3), multiple myeloma (U266), lung (NCI-H460), and breast (MDA-MB-231) cells. Overall, these findings suggest that Tan IIA induces autophagic cell death via activation of AMPK and ERK and inhibition of mTOR and p70 S6K in KBM-5 cells as a potent natural compound for leukemia treatment.
authors.affiliation: Cancer Preventive Material Development Research Center, College of Korean Medicine, Kyung Hee University, Seoul, 130-701, South Korea.
authors.forename: Sun-Mi
authors.initials: SM
authors.lastname: Yun
authors.forename: Ji Hoon
authors.initials: JH
authors.lastname: Jung
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Jeong
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Sohn
authors.forename: Bonglee
authors.initials: B
authors.lastname: Kim
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D045784:Abietanes / Q000494:pharmacology*; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D001343:Autophagy; D045744:Cell Line, Tumor; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000473:pathology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D045784:Abietanes; C021751:tanshinone; C025946:3-methyladenine; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; C448901:ribosomal protein S6 kinase, 70kD, polypeptide 1; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D000225:Adenine
keywords: AMPK; ERK; LC3 II; autophagy; mTOR; p70 S6K; tanshinone IIA